Biochemical Journal最新文献_第2页

Polyamination with spermidine enhances pathogenic tau conformations while reducing filamentous aggregate formation in vitro. 多胺化与亚精胺增强致病性tau构象，同时减少丝状聚集体的形成。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-05-22 DOI: 10.1042/bcj20253079

Mohammed Alhadidy,Rebecca Mueller,Jared Lamp,Nicholas Kanaan

{"title":"Polyamination with spermidine enhances pathogenic tau conformations while reducing filamentous aggregate formation in vitro.","authors":"Mohammed Alhadidy,Rebecca Mueller,Jared Lamp,Nicholas Kanaan","doi":"10.1042/bcj20253079","DOIUrl":"https://doi.org/10.1042/bcj20253079","url":null,"abstract":"Tau is subject to a broad range of post-translational modifications (PTMs) that regulate its biological activity in health and disease, including microtubule (MT) dynamics, aggregation, and adoption of pathogenic conformations. The most studied PTMs of tau are phosphorylation and acetylation; however, the salience of other PTMs is not fully explored. Tissue transglutaminase (TG) is an enzyme whose activity is elevated in Alzheimer's disease (AD). TG action on tau may lead to intramolecular and intermolecular cross-linking along with the incorporation of cationic polyamines [e.g. spermidine (SPD)] onto glutamine residues (Q). Even though SPD levels are significantly elevated in AD, the effects of SPD polyamination on tau biology have yet to be examined. In this work, we describe a method to produce recombinant SPD-modified tau where SPD modifications are mainly localized to Q residues within the N-terminus. MT binding and polymerization assays showed that SPD modification does not significantly alter tau's binding to MTs but increases MT polymerization kinetics. In addition, biochemical and biophysical assays showed that SPD polyamination of tau markedly reduces tau polymerization into filamentous and β-sheet containing aggregates. On the other hand, SPD modification promotes the formation of pathogenic conformations (e.g. oligomerization and misfolding) by tau with or without inducing tau polymerization. Taken together, these data suggest that SPD polyamination of tau enhances its ability to polymerize microtubules and favors the adoption of pathogenic tau conformations but not filamentous aggregates in vitro.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"31 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114168","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cas11 augments Cascade functions in type I-E CRISPR system but is redundant for gene silencing and plasmid interference. Cas11增强了I-E型CRISPR系统中的Cascade功能，但在基因沉默和质粒干扰中是多余的。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-05-22 DOI: 10.1042/bcj20253056

Neha Pandey,Chitra Misra,Devashish Rath

{"title":"Cas11 augments Cascade functions in type I-E CRISPR system but is redundant for gene silencing and plasmid interference.","authors":"Neha Pandey,Chitra Misra,Devashish Rath","doi":"10.1042/bcj20253056","DOIUrl":"https://doi.org/10.1042/bcj20253056","url":null,"abstract":"The structural and mechanistic complexity of Escherichia coli's type I CRISPR-Cas system compared to the multidomain, single effector protein-based type II systems, limits its application in genome editing and silencing. Despite higher prevalence of the type I endogenous systems in bacteria, significant research has focused on improving the type II systems. While the type-I CRISPR system possesses several advantages over others, it may benefit from further studies to simplify the system for ease of use. To enable this, the dispensability of the type-I Cascade components (Cas8, Cas11, Cas7, Cas5, Cas6) for genome editing and silencing applications was evaluated in vivo. We created deletion variants of each of the Cascade components and investigated their effects on gene silencing and plasmid interference in two genetically distinct Escherichia coli lineages, BW25113, a K-12 strain that bears an endogenous, albeit repressed type I-E CRISPR system and BL21, a natural mutant lacking the type I-E CRISPR-Cascade system. Cas8, Cas7 and Cas5 were found to be indispensable for gene silencing and plasmid interference. Dispensability of Cas6, which is involved in crRNA maturation, was strain-dependent. Notably, Cas11 which has no definitive function assigned to it, was found to be dispensable for gene silencing and plasmid interference.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"14 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144114173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Excess Wnt in neurological disease. 神经疾病中过量的Wnt。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-05-16 DOI: 10.1042/BCJ20240265

Danielle M Pascual, Delaram Jebreili Rizi, Harsimran Kaur, Paul C Marcogliese

引用次数: 0

Multifaceted roles of Epac signaling in renal functions. Epac信号在肾功能中的多重作用。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-05-14 DOI: 10.1042/bcj20253103

Oleh Pochynyuk,Kyrylo Pyrshev,Xiaodong Cheng

引用次数: 0

GPCR signaling via cAMP nanodomains. 通过cAMP纳米结构域的GPCR信号传导。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-05-13 DOI: 10.1042/BCJ20253088

Rahul Yadav, Manuela Zaccolo

{"title":"GPCR signaling via cAMP nanodomains.","authors":"Rahul Yadav, Manuela Zaccolo","doi":"10.1042/BCJ20253088","DOIUrl":"10.1042/BCJ20253088","url":null,"abstract":"G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, mediating essential physiological responses through diverse intracellular signaling pathways. When coupled to Gs or Gi proteins, GPCR modulates the synthesis of 3'-5'-cyclic adenosine monophosphate (cAMP), which governs a wide array of processes, ranging from cellular growth and survival to metabolic regulation. Studies have highlighted that cAMP is not uniformly distributed within cells but instead is compartmentalized into highly localized nanodomains. These nanodomains, mostly regulated by phosphodiesterases (PDEs), play a critical role in enabling signal precision and functional effects that are specific to individual stimuli. GPCRs can initiate distinct cAMP responses based on their localization within the cell, with evidence showing that both receptors resident at the plasma membrane and intracellular receptors-including endosomal, Golgi, and nuclear GPCRs-elicit unique cAMP signaling profiles. This review examines the mechanisms underlying GPCR signaling through cAMP nanodomains. We focus on the role of PDE-mediated cAMP degradation in shaping local cAMP signals, the emerging views on mechanisms that may contribute to signal compartmentalization, and the role of intracellular membrane compartments. By exploring these aspects, we aim to highlight the complexity of GPCR signaling networks and illustrate some of the implications for the regulation of cellular function.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"482 10","pages":""},"PeriodicalIF":4.4,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The ascent of AKAPs, from architectural elements to kinase anchors: a perspective. akap的上升，从建筑元素到激酶锚：一个视角。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-05-13 DOI: 10.1042/bcj20253085

Jerome I Falcone,John D Scott

引用次数: 0

Basic features of cellular inositol metabolism as revealed by a newly developed LC-MS method. 新建立的LC-MS方法揭示了细胞肌醇代谢的基本特征。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-05-13 DOI: 10.1042/bcj20253028

Xue Bessie Su,Valeria Fedeli,Guizhen Liu,Meike Amma,Paraskevi Boulasiki,Jingyi Wang,Mariano Bizzarri,Henning Jessen,Dorothea Fiedler,Antonella Riccio,Adolfo Saiardi

{"title":"Basic features of cellular inositol metabolism as revealed by a newly developed LC-MS method.","authors":"Xue Bessie Su,Valeria Fedeli,Guizhen Liu,Meike Amma,Paraskevi Boulasiki,Jingyi Wang,Mariano Bizzarri,Henning Jessen,Dorothea Fiedler,Antonella Riccio,Adolfo Saiardi","doi":"10.1042/bcj20253028","DOIUrl":"https://doi.org/10.1042/bcj20253028","url":null,"abstract":"Inositol plays key roles in many cellular processes. Several studies focussed on the quantitative analysis of phosphorylated forms of inositol, enabled by analytical tools developed to detect these highly charged molecules. Direct measurement of free inositol however has been challenging, because the molecule is uncharged and polar. As a result, the mechanisms maintaining the homeostasis of the inositol remains poorly understood. In this study, we overcome these challenges by developing a quantitative liquid chromatography - mass spectrometry (LC-MS) protocol that can resolve and quantify the three main sugar molecules present inside cells: glucose, fructose, and inositol, as well as distinguish the clinically relevant isomers of inositol: myo-, scyllo-, and chiro-inositol. The quantitative power of the new method was validated by accurately monitoring the changes of inositol levels under well-established conditions in Saccharomyces cerevisiae, where the endogenous synthesis of inositol is increased in the transcription repressor OPI1 knockout opi1D and decreased when wild type yeast is fed with exogenous inositol. The method also revealed a new layer of regulation that takes place when exogenous inositol is added to further boost endogenous inositol synthesis in opi1D in a positive feedback loop. Analyses of mammalian cell lines provided many new insights into inositol metabolism. First, different cell lines displayed distinct sugar profiles and inositol concentrations and responded differently to inositol starvation. Second, mammalian cells can synthesize and import scyllo- but not chiro-inositol. Importantly, our method lent direct evidence to the previous hypothesis that lithium treatment could significantly reduce inositol levels in primary cortical neurons, thus diminishing the pool of free inositol available to the phosphoinositide cycle.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"42 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143945231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unveiling the role of srbA sRNA in biofilm formation by regulating algU, mucA, rhlA, and rsmA in Pseudomonas aeruginosa. 揭示srbA sRNA在铜绿假单胞菌中通过调节algU、mucA、rhlA和rsmA在生物膜形成中的作用。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-05-07 DOI: 10.1042/bcj20240650

Piyali Saha,Samir Kumar Mukherjee,Sk Tofajjen Hossain

{"title":"Unveiling the role of srbA sRNA in biofilm formation by regulating algU, mucA, rhlA, and rsmA in Pseudomonas aeruginosa.","authors":"Piyali Saha,Samir Kumar Mukherjee,Sk Tofajjen Hossain","doi":"10.1042/bcj20240650","DOIUrl":"https://doi.org/10.1042/bcj20240650","url":null,"abstract":"The survival and increasing antimicrobial resistance of various bacteria, including clinically relevant opportunistic pathogen, Pseudomonas aeruginosa, largely depends on their biofilm architectural strength, that makes a challenge to eradicate it. Small RNAs (sRNAs) have been identified as the key modulators in regulating the expression and function of different transcriptional regulators, and the components of regulatory networks involved in bacterial biofilm formation. This study was focused to identify the regulatory role of the srbA sRNA in controlling biofilm formation in P. aeruginosa. srbA was found to be upregulated in both substratum-attached and colony biofilms compared to planktonic growth conditions. Further analysis revealed that srbA overexpressing strain produced more biofilm, whereas a significant reduction in biofilm formation was noted due to srbA deletion. Interestingly, it was also predicted from the study that srbA might regulate the expression of AlgU/MucA, the sigma and anti-sigma factor, involved in biofilm developmental network. Additionally, srbA showed possible interference on the expression of two other important biofilm regulatory genes, rhlA and rsmA. Overall, this research highlights the critical role of srbA sRNA as a central regulator of biofilm formation, and possibly the pathogenicity of P. aeruginosa. These findings might offer potential avenues for developing targeted therapeutic strategies to mitigate biofilm-related infections caused by P. aeruginosa.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"19 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The more we learn, the more diverse it gets: structures, functions and evolution in the Phosphofructokinase Superfamily. 我们了解得越多，它就越多样化：磷酸果糖激酶超家族的结构、功能和进化。

IF 4.1 3区生物学

Biochemical Journal Pub Date : 2025-05-06 DOI: 10.1042/bcj20253024

Jordan A Compton,Wayne M Patrick

{"title":"The more we learn, the more diverse it gets: structures, functions and evolution in the Phosphofructokinase Superfamily.","authors":"Jordan A Compton,Wayne M Patrick","doi":"10.1042/bcj20253024","DOIUrl":"https://doi.org/10.1042/bcj20253024","url":null,"abstract":"The enzyme 6-phosphofructokinase (PFK) phosphorylates d-fructose 6-phosphate, producing d-fructose 1,6-bisphosphate. The canonical version-discovered almost 90 years ago-is ATP-dependent, allosterically regulated and catalyses the first committed step in glycolysis. However, beyond this textbook enzyme, there is fascinating functional and structural variety among PFKs across the tree of life. While PFKs are found in two non-homologous superfamilies, here, we review the universally distributed enzymes in one, the Phosphofructokinase Superfamily. We focus on summarising the diversity within this superfamily. A key partition regards the identity of the phosphate donor, which can be ATP or inorganic pyrophosphate (PPi). Considerable insights into functional and evolutionary aspects of the ATP- and PPi-dependent PFKs have come through structural biology, with 45 structures now available in the Protein Data Bank. One recent highlight was the use of cryoEM and molecular dynamics simulations to illuminate the structural basis of allosteric regulation in human liver PFK. Others were to explore interactions of drug-like small molecules with the PFKs from Trypanosoma brucei and human liver, revealing new routes to antibiotics and immune modulators, respectively. In contrast with the ATP-dependent enzymes, PPi-dependent PFKs are typically non-allosteric and catalyse a readily reversible reaction. Some also play an additional physiological role by phosphorylating d-sedoheptulose 7-phosphate. We discuss why these properties are plausibly ancestral. Finally, we also emphasise how much remains to be discovered. For example, the 45 experimentally determined structures are from only 14 species. Nine decades in, it is still a great time to be studying PFK.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"15 1","pages":"467-483"},"PeriodicalIF":4.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Single-molecule observations of human small heat shock proteins in complex with aggregation-prone client proteins. 人小热休克蛋白与易聚集的客户蛋白复合物的单分子观察。

IF 4.4 3区生物学

Biochemical Journal Pub Date : 2025-05-06 DOI: 10.1042/BCJ20240473

Lauren Rice, Nicholas Marzano, Dezerae Cox, Bailey Skewes, Antoine M van Oijen, Heath Ecroyd

{"title":"Single-molecule observations of human small heat shock proteins in complex with aggregation-prone client proteins.","authors":"Lauren Rice, Nicholas Marzano, Dezerae Cox, Bailey Skewes, Antoine M van Oijen, Heath Ecroyd","doi":"10.1042/BCJ20240473","DOIUrl":"10.1042/BCJ20240473","url":null,"abstract":"Small heat shock proteins (sHsps) are molecular chaperones that act to prevent the aberrant aggregation of misfolded proteins. Whilst it is suggested that sHsps prevent aggregation by binding to misfolded client proteins, the dynamic and heterogeneous nature of sHsps has hindered attempts to establish the mechanistic details of how sHsp-client protein complexes form. Single-molecule approaches have emerged as a powerful tool to investigate dynamic and heterogeneous interactions such as those that can occur between sHsps and their client proteins. Here, we use total internal reflection fluorescence microscopy to observe and characterise the complexes formed between model aggregation-prone client proteins (firefly luciferase, rhodanese and chloride intracellular channel 1 protein), and the human sHsps αB-crystallin (αB-c; HSPB5) and Hsp27 (HSPB1). We show that small (monomeric or dimeric) forms of both αB-c and Hsp27 bind to misfolded or oligomeric forms of the client proteins at early stages of aggregation, resulting in the formation of soluble sHsp-client complexes. Stoichiometric analysis of these complexes revealed that additional αB-c subunits accumulate onto pre-existing sHsp-client complexes to form larger species - this does not occur to the same extent for Hsp27. Instead, Hsp27-client interactions tend to be more transient than those of αB-c. Elucidating these mechanisms of sHsp function is crucial to our understanding of how these molecular chaperones act to inhibit protein aggregation and maintain cellular proteostasis.","PeriodicalId":8825,"journal":{"name":"Biochemical Journal","volume":"482 9","pages":"413-432"},"PeriodicalIF":4.4,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0